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Objective: Both isoniazid preventive therapy (IPT) and antiretroviral therapy (ART) reduce tuberculosis risk in individuals living with HIV. We sought to estimate the broader, population-wide impact of providing a pragmatically implemented 12-month IPT regimen to ART recipients in a high-burden community., Design: Dynamic transmission model of a tuberculosis (TB)-HIV epidemic, calibrated to site-specific, historical epidemiologic and clinical trial data from Khayelitsha, South Africa., Methods: We projected the 5-year impact of delivering a 12-month IPT regimen community-wide to 85% of new ART initiators and 15%/year of those already on ART, accounting for IPT-attributable reductions in TB infection, progression, and transmission. We also evaluated scenarios of continuously-delivered IPT, ongoing ART scale-up, and lower tuberculosis incidence., Results: Under historical (early 2010) ART coverage, this ART-linked IPT intervention prevented one tuberculosis case per 18 [95% credible interval (CrI) 11-29] people treated. It lowered TB incidence by a projected 23% (95% CrI 14-30%) among people receiving ART, and by 5.2% (95% CrI 2.9-8.7%) in the total population. Continuous IPT reduced the number needed to treat to prevent one case of TB to 10 (95% CrI 7-16), though it required 74% more person-years of therapy (95% CrI 64-94%) to prevent one TB case, relative to 12-month therapy. Under expanding ART coverage, the tuberculosis incidence reduction achieved by 12-month IPT grew to 7.6% (95% CrI 4.3-12.6%). Effect sizes were similar in a simulated setting of lower TB incidence., Conclusions: IPT in conjunction with ART reduces tuberculosis incidence among those who receive therapy and has additional impact on tuberculosis transmission in the population.

Background: In HIV-uninfected individuals, isoniazid preventive therapy (IPT) has been associated with long-term protection against tuberculosis (TB). For HIV-infected/antiretroviral therapy (ART)-naive individuals, high TB rates have been observed following completion of IPT, consistent with a lack of 'cure' of infection. Recent trial data of IPT among HIV-infected individuals on ART in Khayelitsha, South Africa, have suggested that the effect of IPT persisted following completion of IPT., Methods: Using mathematical modelling, we explored if this increased duration of protection may be due to an increased curative ability of IPT when given in combination with ART. The model was used to estimate the annual risk of infection and proportion of individuals whose latent infection was 'cured' by IPT, defined such that they must be reinfected to be at risk of disease., Results: The estimated annual risk of infection was 4.0% (2.6-5.8) and the estimated proportion of individuals whose latent Mycobacterium tuberculosis infection was cured following IPT was 35.4% (2.4-76.4), higher than that previously estimated for HIV-infected/ART-naive individuals. Our results suggest that IPT can cure latent M. tuberculosis infection in approximately one-third of HIV-infected individuals on ART and therefore provide protection beyond the period of treatment., Conclusion: Among HIV-infected individuals on ART in low incidence settings, 12 months of IPT may provide additional long-term benefit. Among HIV-infected individuals on ART in high incidence settings, the durability of this protection will be limited because of continued risk of reinfection, and continuous preventive therapy together with improved infection control efforts will be required to provide long-term protection against TB.

Objectives: To study whether in-vivo recruitment of dendritic cells in response to antigen administration in the skin is altered during HIV-1 infection., Design: Skin punch biopsies were collected from HIV-1-positive as well as seronegative individuals at 48 h after intradermal injection of inactivated antigens of mumps virus, Candida albicans, or purified protein derivate (PPD) from Mycobacterium tuberculosis., Methods: Cryosections were analyzed by in-situ staining and computerized imaging., Results: Control skin biopsies showed that there was no difference in the number of skin-resident dendritic cells between seronegative and HIV-1-positive individuals. Antigen injection resulted in substantial infiltration of dendritic cells compared to the frequencies found in donor-matched control skin. In HIV-1-positive individuals, CD123(+)/CD303(+) plasmacytoid dendritic cells and CD11c myeloid dendritic cells, including the CD141(+) cross-presenting subset, were recruited at lower levels compared to healthy controls in response to PPD and mumps but not C. albicans. The level of dendritic cell recruitment correlated with the frequencies of T cells infiltrating the respective antigen sites. Ki67(+) cycling T cells at the injection sites were much more frequent in response to each of the antigens in the HIV-1-positive individuals, including those with AIDS, compared to healthy controls., Conclusion: Multiple dendritic cell subsets infiltrate the dermis in response to antigen exposure. There was no obvious depletion or deficiency in mobilization of dendritic cells in response to antigen skin tests during chronic HIV-1 infection. Instead, the levels of antigen-specific memory T cells that accumulate at the antigen site may determine the level of dendritic cell infiltration.

Objective: Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a frequent complication of antiretroviral therapy in resource-limited countries. We aimed to assess whether a 4-week course of prednisone would reduce morbidity in patients with paradoxical TB-IRIS without excess adverse events., Design: A randomized, double-blind, placebo-controlled trial of prednisone (1.5 mg/kg per day for 2 weeks then 0.75 mg/kg per day for 2 weeks). Patients with immediately life-threatening TB-IRIS manifestations were excluded., Methods: The primary combined endpoint was days of hospitalization and outpatient therapeutic procedures, which were counted as one hospital day., Results: One hundred and ten participants were enrolled (55 to each arm). The primary combined endpoint was more frequent in the placebo than the prednisone arm {median hospital days 3 [interquartile range (IQR) 0-9] and 0 (IQR 0-3), respectively; P = 0.04}. There were significantly greater improvements in symptoms, Karnofsky score, and quality of life (MOS-HIV) in the prednisone vs. the placebo arm at 2 and 4 weeks, but not at later time points. Chest radiographs improved significantly more in the prednisone arm at weeks 2 (P = 0.002) and 4 (P = 0.02). Infections on study medication occurred in more participants in prednisone than in placebo arm (27 vs. 17, respectively; P = 0.05), but there was no difference in severe infections (2 vs. 4, respectively; P = 0.40). Isolates from 10 participants were found to be resistant to rifampicin after enrolment., Conclusion: Prednisone reduced the need for hospitalization and therapeutic procedures and hastened improvements in symptoms, performance, and quality of life. It is important to investigate for drug-resistant tuberculosis and other causes for deterioration before administering glucocorticoids.